Integrating fragment assembly and biophysical methods in the chemical advancement of small-molecule antagonists of IL-2: An approach for inhibiting protein-protein interactions
Integrating fragment assembly and biophysical methods in the chemical advancement of small-molecule antagonists of IL-2: An approach for inhibiting protein-protein interactions
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DOI：
10.1021/jm049967u
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发表时间：
2004-06-03
影响因子：
7.3
通讯作者：
Arkin, MR
中科院分区：
文献类型：
--
作者：
Raimundo, BC;Oslob, JD;Arkin, MR
片段组装已显示出发现困难靶点（包括蛋白质-蛋白质相互作用）的小分子拮抗剂的前景。在这里，我们描述了一种用于鉴定白细胞介素-2（IL-2）/IL-2受体（IL-2 R α）相互作用的60 nM抑制剂的方法。通过使用基于片段的方法，具有毫摩尔亲和力的化合物被进化为具有低微摩尔活性的命中系列，并且这些化合物被优化为具有纳摩尔亲和力的铅系列。片段组装不仅对命中识别有用，而且对引线优化有用。在整个发现过程中，生物物理学方法和结构生物学证明化合物在IL-2受体结合位点可逆地结合IL-2。
Fragment assembly has shown promise for discovering small-molecule antagonists for difficult targets, including protein-protein interactions. Here, we describe a process for identifying a 60 nM inhibitor of the interleukin-2 (IL-2)/IL-2 receptor (IL-2Ralpha) interaction. By use of fragment-based approaches, a compound with millimolar affinity was evolved to a hit series with low micromolar activity, and these compounds were optimized into a lead series with nanomolar affinity. Fragment assembly was useful not only for hit identification, but also for lead optimization. Throughout the discovery process, biophysical methods and structural biology demonstrated that compounds bound reversibly to IL-2 at the IL-2 receptor binding site.